Systemic lupus erythematosis (SLE) is a chronic autoimmune disease that is estimated to affect as many as half a million people in the United States. Over the past 5 years, we have produced and characterized a unique collection of B6-congenic strains derived from the NZM2410 lupus-prone mouse model of human SLE. Our current proposal is focused on elucidating the specific genetic and cellular mechanisms that mediate the pathogenic manifestation expressed in these pathways. Project 1 (P.I.:E.K. Wakeland) is focused predominantly on identifying genes in the Sle1 cluster that are responsible for the loss of immunologic tolerance to chromatin antigens. The essential congenic recombinant strains required for the positional cloning of these genes have been produced and our team of investigators are poised to identify at least two of the genes that are responsible for breaking tolerance to nuclear antigens in the NZM210 mouse. The importance of identifying these murine genes is strengthened considerably by recent data suggesting that their human homologues may play a key role in susceptibility to SLE, especially associated with the Sle2 genetic interval. These studies will provide important new insights into the genetics of this complex susceptibility C. Mohan) will focus on elucidating the cellular and molecular mechanisms responsible for end organ damage as a consequence of systemic autoimmunity. These studies will utilize the congenic strains we have produced to elucidate the pathogenic mechanisms responsible for the development of severe kidney disease. Finally, Project 4 (P.I. E. Sobel) is focused on characterizing the cellular mechanisms that are dysregulated monocyte/dendritic cell lineage. The unifying theme of all of these projects residues in their focus on characterizing the properties of our collection of B6-congenic strains. The predominant research synergism in our efforts comes from the interfacing of expertise in mouse genetics with valuable new systems with which to characterize the immunologic processes responsible for autoimmune pathogenesis. The cellular immunologists, in turn, identify and characterize valuable new phenotypes that can be used for the characterization of an extremely valuable collection of mouse strains. In addition, several of the specific aims in each of the projects in this program project arose as the result of insights generated via the collaborative interactions of these investigators. We believe that these investigations will provide important insights into the manner in which genetic predisposition mediates the development of autoimmunity in human SLE.